The overall goal of this proposal is to dissect the genetic determinants of individual variation in response to medications used routinely for the treatment and prevention of cardiovascular disease (CVD). Projects will be performed by an established multidisciplinary group that has a track record of publication and productivity, collegial interactions with outside groups, including other NIH funded multi-center networks, and a history of data sharing. Project 1: Pharmacogenomics of anti-platelet agents for CVD prevention: This project seeks to identify specific gene variants that predict response to clopidogrel (Plavix) for the 1 degree and 2 degree prevention of CV events. We will build upon our large ongoing HAPI Heart Study in which 1,000 related Old Order Amish subjects, all of whom have been extensively characterized with respect to CVD (including response to aspirin) and in whom an 800 short tandem repeat marker genome scan has been completed. We propose to treat these same subjects with clopidogrel and to obtain measures of platelet aggregation and function. We will (1) determine the frequency and heritability of clopidogrel response and the relationship between clopidogrel resistance and aspirin resistance;(2) exhaustively define sequence variation and haplotype structure of 100 candidate genes and perform linkage and association analysis of SNPs/haplotypes with platelet function phenotypes;and (3) perform genome-wide linkage analysis to identify chromosome regions (and ultimately genes) linked to clopidogrel response. The proposed studies will provide important insights into clopidogrel and TZD response, will have important implications for the prevention and treatment of CVD in millions of Americans.